IN-VIVO TOXICOLOGICAL EFFECTS OF REL-A ANTISENSE PHOSPHOROTHIOATES INCD-1 MICE

To characterize the in vivo toxicity of phosphorothioate antisense oli gonucleotides against rel A (p65 subunit of NF-kappaB transcription fa ctor), forty-eight 6-week-old CD-1 mice were split into 4 groups (6/se x/group) receiving vehicle (phosphate-buffered saline) or doses of 50, 100, and 150 mg/kg of rel A antisense oligonucleotides intraperitonea lly 3 times weekly for 2 weeks. Clinical signs of toxicity included we akness, and decreased motor activity and food consumption with body we ight loss. Mortality occurred in 7 of 12 mice in the 150-mg/kg group a nd in 2 of 12 mice in the 100-mg/kg group, most of which died within t he first 2 to 4 days of treatment. The remaining mice were necropsied on day 15. The major hematological finding was severe dose-dependent t hrombocytopenia. The liver enzyme levels were mildly elevated in the s erum of mid- and high-dose animals. At necropsy, increased spleen and liver weights were observed in treated mice, some of which also had mi ld pleural and/or peritoneal effusions. Histopathological examination revealed the likely cause of death to be acute renal failure due to re nal cortical or tubular necrosis. Treatment-related changes were also found in the liver, spleen, bone marrow, and several other organs. In summary, the kidney, liver, and bone marrow (megakaryocytic lineage) w ere identified as the major target organs for toxicity with rel A anti sense therapy.